Platinum drugs (cisplatin, cis-diamminedichloroplatinum(II), CDDP; carboplatin, diammine[1,1-cyclobutanedicarboxylato]platinum(II); and oxaliplatin, [(1R,2R)-cyclohexane-1,2diamine](ethanedioato)platinum(II); FIG. 1) are widely used in the clinic and the prototype cisplatin still represents an antineoplastic drug with highly curative effects in a solid malignancy such as testicular cancer (Cisplatin: Chemistry and Biochemistry of a Leading Anticancer Drug. (Lippert, B., Eds.). Verlag Helvetica Chimica Acta, Zürich, 2000, 563 pp.; Jakupec, M. A., et al., Dalton Trans. 2008, 183-194; Kelland, L., Nat. Rev. Cancer 2007, 7, 573-584; Reedijk, J., Eur. J. Inorg. Chem. 2009, 1303-1312; Wong, E., et al., Chem. Rev. 1999, 99, 2451-2466; Hall, M. D., et al., J. Med. Chem. 2007, 50, 3403-3411; and Wheate, N. J., et al., Dalton Trans. 2010, 39, 8113-8127). The complex [PtCl2(cis-1,4-DACH)] (DACH=diaminocyclohexane), [SP-4-2-(cis)]-dichloro(1,4-cyclohexanediamine-N,N′)platinum, compound 1 (FIG. 1), contains an isomeric form of the diaminocyclohexane ligand found in oxaliplatin and has been widely investigated as a potential new platinum anticancer drug. Compound 1 also called “Kiteplatin” based on its structural features (Ranaldo, R., et al., Inorg. Chem. 2008, 47, 2820-2830) resembling a parachute (the cis-1,4-DACH ligand) on a skydiver (the metal). U.S. Pat. No. 4,999,444 discloses a series of novel neutral mixed ligand platinum (II) and platinum (IV) complexes including [SP-4-2-(cis)]-dichloro(1,4-cyclohexanediamine,N,N′)platinum.
The first paper reporting the in vitro and in vivo activities of compound 1 was published by Hoeschele, J. D., et al, J. Med. Chem. 1994, 37, 2630-2636. The in vitro growth inhibition data indicated that compound 1 exhibited potent activity in sensitive L1210 and P388 cell lines and that the compound also appeared more potent than cisplatin (based on ID50 values) against all tested Pt-resistant cell lines with the only exception of the cisplatin-resistant cell lines L1210PtR4 and L1210DDP5 (partial cross-resistance) and the oxaliplatin-resistant cell line L1210DACH. In vivo, compound 1 proved to be more dose potent than cisplatin (based on % T/C values) against the parental L1210 and P388 murine leukemias. Compound 1 also retained a significant activity against sublines derived from L1210 and P388 and made resistant to cisplatin. Both compound 1 and cisplatin produced equivalent activity against B16 melanoma and M5076 sarcoma, while cisplatin was more active than compound 1 against colon carcinoma 26 at equitoxic doses. These initial data suggested that the spectrum of activity of compound 1 could have been different from those of cisplatin and oxaliplatin.
Two years later, Shamsuddin, S., et al., J. Inorg. Biochem. 1996, 61, 291-301 reported the in vitro cytotoxicity of compound 1 against murine leukemia L1210 and human ovarian cancer A2780 cells. The compound was found to be more active than cisplatin and tetraplatin (PtIVCl4(1R,2R-DACH)) in both cell lines (the human A2780 cell line being more sensitive). The high potency and the high solubility in water of compound 1 made this compound an ideal lead for further studies. Khokhar and collaborators also explored PtIV(cis-1,4-DACH) derivatives (Shamsuddin, S., et al., J. Inorg. Biochem. 1998, 71, 29-35) and found that, among a series of complexes having the general formula cis,cis,trans-[PtIVCl2(cis-1,4-DACH)L2] (L=CH3(CH2)nCOO—, n=0-8), cis,cis,trans-[PtIVCl2(cis-1,4-DACH)(CH3COO)2] was the most active in the murine L1210 leukemia model. Khokhar and colleagues also prepared and characterized monofunctional (Ali, M. S., et al., J. Inorg. Biochem. 2003, 96, 452-456) and bifunctional (Shamsuddin, S., et al., Polyhedron. 2007, 26, 637-644) adducts of compound 1 with nucleobases as models for DNA binding of these Pt antitumor drugs (Wang, D., et al., Nat. Rev. Drug Discovery 2005, 4, 307-320 and Fuertes, M. A., et al., Chem. Rev. 2003, 103, 645-662).
A peculiar feature of platinum-coordinated cis-1,4-DACH is the formation of a seven-membered chelate ring, which is larger than the usually encountered five- and six-membered rings (X-ray diffraction data) (Hoeschele, J. D., et al, J. Med. Chem. 1994, 37, 2630-2636 and Ranaldo, R., et al., Inorg. Chem. 2008, 47, 2820-2830). This results in a very large bite angle (≧97° that could affect mobility of cis ligands. Indeed researchers investigated the (cis-1,4-DACH)PtG2 system (G=two untethered guanine bases) (Ranaldo, R., et al., Inorg. Chem. 2008, 47, 2820-2830) and by lowering the temperature, were able to observe the presence of different rotamers in solution (two HT, head-to-tail, and one HH, head-to-head, conformers are possible in aqueous solution) (Natile, G., et al., Coord. Chem. Rev. 2006, 250, 1315-1331 and references therein).
The unique antitumor activity of compound 1 was further investigated with reference to: cell entry, reaction with sulfur-containing compounds, binding to DNA, and processing of DNA adducts by proteins (including DNA repair enzymes) (Kasparkova, J., et al., Biochem. Pharmacol. 2010, 79, 552-564). In particular, compared to cisplatin, compound 1 revealed: i) improved cytotoxicity (3.4-5.4-fold greater) and enhanced cellular uptake (ca. 1.5-fold greater) in human ovarian A2780 cancer cell line; ii) enhanced rate but similar sequence preference for DNA binding in cell-free media; iii) identical DNA interstrand cross-linking efficiency (6%); iv) similar bending (32°) but enhanced local DNA unwinding (ca. 1.5-fold greater) for 1,2-GG-intrastrand cross-links; v) markedly enhanced inhibition of DNA polymerase accompanied by significantly lower efficiency of DNA repair.
Later, in order to determine how the Y-family translesion DNA polymerase η (Polη) processes lesions generated by complex 1, model systems employing a DNA double-base lesion derived from 1,2-GG intrastrand crosslinks of this complex were investigated (V. Brabec, J. Malina, N. Margiotta, G. Natile, J. Kasparkova. Chem. Eur. J. 2012, 18, 15439-15448). The catalytic efficiency of Polη for the insertion of correct dCTP, with respect to the other incorrect nucleotides, opposite the 1,2-GG cross-link was markedly reduced by the cis-1,4-DACH carrier ligand. This reduced efficiency of Polη to incorporate the correct dCTP could be due to a more extensive DNA unstacking and deformation of the minor groove induced in the DNA by the cross-link of bulky complex 1. The major products of the bypass of this doublebase lesion produced by complex 1 by Polη resulted from misincorporation of dATP opposite the platinated G residues. The results of the investigation supported the thesis that the misincorporation could be due to sterical effects of the bulkier cis-1,4-DACH ligand hindering the formation of the Polη-DNA-incoming nucleotide complex. Calorimetric analysis suggested also that thermodynamic factors may contribute to the forces that governed enhanced incorporation of the incorrect dATP by Polη as well.
Colorectal cancer is at the top of the list of the most common cancers worldwide, with around 1 million new cases diagnosed every year (Van Cutsem, E., et al., J. Clin. Oncol. 2007, 25, 1658-1664). Early stage colorectal cancer is frequently curable with surgery, but the appearance of metastases leads to unresectable tissues with fatal consequences for the patient (Saltz, L. B., et al., J. Clin. Oncol. 2004, 22, 1201-1208). The best outcome in the therapy of metastatic colorectal cancer is obtained by the use of 5-fluorouracil, oxaliplatin, and irinotecan. More recently, biologic therapies have also proved to be effective in prolonging the median survival time (Sobrero, A. F., et al., J. Clin. Oncol. 2008, 26, 2311-2319).
Presently, apart from oxaliplatin, there are no other drugs in advanced clinical development which appear to be active against colorectal cancer and that could be used for the treatment of patients with oxaliplatin-refractory colorectal cancer.
Thus, there is considerable interest and an urgent need to find therapies to treat and or prevent oxaliplatin-refractory colorectal cancer. The present invention answers the need by providing compounds of formula I and formula II and in particular compound 1. Therefore, compound 1 was evaluated against human colorectal cancer cells and, in particular, colorectal cancer cells resistant to oxaliplatin (Margiotta, N., et al., J. Med. Chem. 2012, 55(16), pp 7182-7192). We surprisingly and unexpectedly found that compounds of formula I and formula II and in particular compound 1 was effective in treating refractory colorectal cancer and especially in circumventing cisplatin and oxaliplatin resistance in colorectal cancer.